Many of the investigations in this genetic epidemiology project arise from observations in families at high risk of cancer or in other etiologic studies. A pilot study to follow-up patients from a case-control study of 718 non-Hispanic white patients with cutaneous melanoma from melanoma clinics in Philadelphia and San Francisco is being planned. Questionnaire data, tumor, and DNA from a case-control study of 183 incident melanoma cases and 179 controls conducted in North-Eastern Italy were used to evaluate the melanocortin-1 receptor (MC1R) gene, the major regulator of human pigmentation, and somatic mutations of the BRAF oncogene. In subjects with melanoma arising on sun exposed areas of the body and with limited chronic solar damage, we found a strong association between MC1R germline variants and melanoma with somatic mutations in the BRAF oncogene. We confirmed this association in an independent population. Data from other Italian populations have been collected to extend the analyses of association between melanoma risk and pigmentation and immune-related genes;evaluation of these additional populations is in process. One of the potential pathways that leads to the development of melanoma includes the loss of regulation of common melanocytic nevi, which acquire atypic or dysplastic characteristics that can further evolve in neoplasia. To study this pathway, we are currently collecting multiple tissue samples of normal skin, common melanocytic nevi, dysplastic nevi, melanoma and metastasis from melanoma from the same subjects from Italy and Spain. We are planning to study the expression and presence of mutations in multiple genes of the cell cycle, telomere, and transduction pathways in the serial tissue samples and germline DNA to explore the mechanisms involved in melanoma development through nevi. Relatives of 365 of the glioma cases from a DCEG comprehensive case-control study of adults with brain tumors were interviewed about personal/family medical history and other risk factors. Analyses to examine the risk of cancer among the first degree relatives compared to population controls have been completed;write-up of the results is in process. Examination of questionnaire data from a retrospective single institution study of childhood medulloblastoma showed little evidence for increased cancer risks among relatives of medulloblastoma patients. Chordoma is a rare primary malignant bone tumor that arises mainly in the axial skeleton from rests of embryonic notochordal stem cells that failed to undergo normal regression. We collaborated with the Department of Radiation Oncology, Massachusetts General Hospital, Boston, to identify chordoma families to help map and identify a chordoma susceptibility gene. Evaluation of the families is in progress. An expanded project has been developed to collect personal and family medical history, buccal cells and slides of tumor tissue from sporadic chordoma patients from throughout the United States. The project will collect up to 100 patients diagnosed with chordoma at any age and anatomic site. In collaboration with Yale University Tissue Microarray (TMA) core facility, we have successfully built TMAs of 1,500 invasive tumors collected from the Polish Breast Cancer Study. We have immunohistochemically (IHC) stained a subset of these tumors (N=842) for 18 molecular markers involved in hormone biosynthesis, metabolism, and receptor mediated pathways. Analyses of these markers suggest that risk factors for breast cancer may vary by molecular subtypes and by hormone pathways characterized by co-expression of the hormonal markers. We have also stained all TMAs for six markers (ER-alpha, ER-beta, PR, HER2, EGFR, and CK5) using a newly developed Automated Quantitative Analysis (AQUA). Comparison of the two approaches (AQUA and IHC) demonstrated AQUA analyses of tumors represented in TMAs provide reliable, quantitative measures of marker expression. We have also compared some commercially available imaging analysis software to pathologists measurements and our data suggested that automated analysis of IHC markers represents a promising approach for analyzing large numbers of breast cancer tissues in epidemiologic investigations. We are expanding our analyses of risk factor heterogeneity by tumor subtypes to a pooled analysis of 34 studies participating in the Breast Cancer Association Consortium (BCAC). In addition to the analysis of invasive tumors, we are also measuring marker expression in normal breast epithelial cells (terminal duct lobular units, TDLUs) in 150 Polish breast cancer cases and correlating marker data with risk factors, clinical characteristics and morphology (TDLU involution). In addition to TMA analyses of candidate markers in fixed tissues, we have conducted tumor profiling for gene expression, CpG methylation, and copy number changes in frozen tumors from a subset of Polish breast cancer cases to better define molecular subtypes that are associated with distinct etiologic pathways. Renal cell carcinoma (RCC) rates in Central and Eastern Europe are among the highest in the world. The von Hippel Lindau-Hypoxia Inducible Factor (VHL-HIF) pathway has been implicated in kidney cancer tumorigenesis. We investigated the role of common variants in genes in the VHL-HIF pathway in the susceptibility of sporadic RCC and clear cell RCC. We identified common genetic variants in genes in the VHL-HIF pathway associated with kidney cancer risk. Evaluation of the genetic variants has been completed;write-up of the results is in process. We are continuing to conduct studies using the Swedish linked registry data to define lymphoid malignancies that co-aggregate in families and to detect immune-related and inflammatory conditions (based on hospitalization records) that pre-dispose to lymphoid malignancies. We found an increased risk of lymphoplasmacytic lymphoma (LPL). Waldenstrom macroglobulinemia (WM) was associated with a personal history of several autoimmune diseases, especially those with systemic involvement (OR=1.9, 95%CI: 1.3-2.7). Several infections were also associated with increased risk of LPL-WM. A family history of Sjogren syndrome was also associated with LPL-WM (OR=5.0, 95%CI: 2.1-12.0) suggesting a common genetic predisposition to autoimmune diseases and lymphoma. We have found that hospitalization for infection in infancy is associated with later development of aggressive B-cell NHLs but not Hodgkin lymphoma. Thus, infection in infancy could be a surrogate marker of immune system defects. We have found that autoimmune diseases and infections are also associated with myeloid malignancies. For example, AML and MDS patients show a significant association with several autoimmune diseases and infections that are evident as much as 5 years before the onset of leukemia/myelodysplasia, respectively.